Project Summary Stargardt disease (STGD) is a rare, inherited, degenerative disease of the retina, reducing visual acuity to 20/200 or worse beginning in the first 3 decades of life. Calculated estimates indicate STGD affects roughly 41,119 patients in the US, making it the most common hereditary macular dystrophy. There are currently no approved treatments for STGD anywhere worldwide. STGD is characterized by an excessive build-up of lipofuscin at the level of the retinal pigment epithelium (RPE). The visual cycle isomerohydrolase, RPE65, plays a key role in this chemical pathway. Inhibition of RPE65 reduces accumulation of lipofuscin and its component bisretinoids; hence, it may slow the progression of STGD. Acucela, Inc. (Acucela) has developed emixustat hydrochloride (emixustat), an orally administered inhibitor that targets RPE65. Acucela is now conducting the SeaSTAR study, a phase 3 multicenter, randomized, double-masked study to compare the efficacy and safety of emixustat with placebo for the treatment of macular atrophy secondary to STGD. The hypothesis is that emixustat slows the progression of STGD by reducing retinal pathology caused by the accumulation of lipofuscin. The data obtained in the proposed study will significantly advance the STGD field in two ways. If emixustat demonstrates efficacy by reducing the rate of disease progression, it would present a major step forward in developing the first available treatment for STGD patients. Additionally, the SeaSTAR study will contribute substantially to the understanding of the natural history of STGD due to the large number of patients on placebo. The most significant obstacle in the field of inherited retinal diseases such as STGD has been an inadequate understanding of the natural history of these diseases. While recent advances have provided important data on certain aspects of the natural history of the disease, information in particular on additional functional and structural endpoints as well as quality-of-life measures is still lacking. The SeaSTAR study will gather data on these measures to fill this knowledge gap. Confirming the hypothesis that emixustat reduces the accumulation of lipofuscin would provide invaluable proof-of-concept that RPE65 is a valid therapeutic target for further drug development. Additionally, both the US and European governmental drug approval agencies have agreed that positive results will be evidence of safety and efficacy that can be used for marketing approval of emixustat as the first approved treatment available for STGD. The primary efficacy endpoint will be the mean rate of change in mm2/year from baseline in the total area of macular atrophy lesion(s) in the study eye. Secondary endpoints include, among several, safety and tolerability evaluations, mean change from baseline in retinal sensitivity, and quality-of-life measurements such as the Functional Reading Independence Index. Exploratory endpoints are mean change from baseline in extent of abnormal near-infrared fundus autofluorescence and the relationship between pharmacokinetic exposure of emixustat and efficacy response. In summary, the results of this study will at minimum expand the field of knowledge of the natural history of STGD and if fully successful provide the first evidence of a treatment effect in this debilitating, blinding disease.